Gene set enrichment analysis provides insight into novel signalling pathways in breast cancer stem cells.
Gene set enrichment analysis provides insight into novel signalling pathways in breast cancer stem cells.
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DOI：
10.1038/sj.bjc.6605468
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发表时间：
2010-01-05
影响因子：
8.8
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中科院分区：
文献类型：
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肿瘤起始细胞(TICs)或癌症干细胞可以作为一小部分存在于恶性组织中。抽动中激活的信号通路在肿瘤发生中的作用尚不完全清楚。用CD24和CD44对几个乳腺癌细胞株进行了分选，CD24和CD44是乳腺癌TIC丰富的已知标记。用分离的细胞分析肿瘤的发生，并对总RNA进行基因表达谱和基因集浓缩分析(GSEA)。我们发现，几种乳腺癌细胞系都有少量的CD24CD24Low/CD44+细胞，其中可能存在TICS，并在异种移植模型中证实了TICS的特性。GSEA显示，CD24CD24Low/CD44+细胞群体富含参与转化生长因子-β、肿瘤坏死因子和干扰素反应途径的基因。此外，我们还发现在CD24CD24Low/κ+细胞中存在核因子-κB(NF-−B)活性，这是以前没有发现的。此外，核因子-κB抑制剂脱羟甲氧奎诺米星(DHMEQ)可在体内阻止CD24CD24Low/CD44+细胞的肿瘤发生。我们的发现表明，使用GSEA识别的信号通路有助于识别TIC样细胞的分子靶点和生物标记物。
Tumour-initiating cells (TICs) or cancer stem cells can exist as a small population in malignant tissues. The signalling pathways activated in TICs that contribute to tumourigenesis are not fully understood. Several breast cancer cell lines were sorted with CD24 and CD44, known markers for enrichment of breast cancer TICs. Tumourigenesis was analysed using sorted cells and total RNA was subjected to gene expression profiling and gene set enrichment analysis (GSEA). We showed that several breast cancer cell lines have a small population of CD24−/low/CD44+ cells in which TICs may be enriched, and confirmed the properties of TICs in a xenograft model. GSEA revealed that CD24−/low/CD44+ cell populations are enriched for genes involved in transforming growth factor-β, tumour necrosis factor, and interferon response pathways. Moreover, we found the presence of nuclear factor-κB (NF-κB) activity in CD24−/low/CD44+ cells, which was previously unrecognised. In addition, NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) prevented tumourigenesis of CD24−/low/CD44+ cells in vivo. Our findings suggest that signalling pathways identified using GSEA help to identify molecular targets and biomarkers for TIC-like cells.